Introduction: Beyond Genetics

• Levin’s group studies how evolution uses a “multiscale competency architecture” and focuses on the “software” level (bioelectricity) rather than just the “hardware” (DNA).
• Biology utilizes “agential materials”: Cells have inherent goals and problem-solving abilities, not just passive components.
• Dynamic, robust anatomical homeostasis is a form of cellular collective intelligence, problem-solving in “morphospace.”
• Developmental bioelectricity is a key “cognitive glue” coordinating cells to achieve large-scale anatomical outcomes.

The “Anatomical Compiler” – A Regenerative Medicine Goal

• The long-term goal is an “anatomical compiler”: Software to translate a desired anatomical design into stimuli that guide cells to build it.
• This would solve major medical problems like birth defects, injury, cancer, and aging by controlling cell group construction.
• Current limitations: We lack models to predict anatomy from genomes alone, even in chimeric embryos (e.g., axolotl-frog hybrids).
• Medicine focuses on “hardware” (genetics, pathways); understanding “software” (cellular decision-making) is crucial, especially in novel situations.

Cellular Intelligence and Robust Development

• Embryogenesis isn’t hardwired: Cutting an embryo in half yields two normal individuals, showing adaptability.
• Cells adjust to internal changes: Kidney tubule cells adapt to varying sizes, maintaining correct lumen diameter through different mechanisms.
• Regeneration demonstrates anatomical homeostasis: A salamander limb regrows to the correct size and stops.
• “Picasso tadpoles” with misplaced facial features develop into mostly normal frogs, demonstrating error correction.
• Cells form networks, scaling up homeostatic loops. Single-cell goals (pH, hunger) expand to tissue/organ goals (limb length, finger count). Cancer involves cells reverting to primitive, single-cell goals.

Bioelectricity: The Cellular Communication Network

• Cells use bioelectricity, like brains, but predating nervous systems: Ion channels create voltage potentials; electrical synapses (gap junctions) facilitate communication.
• Early embryos use electrical networks to guide body plan development in “morphospace.”
• Levin’s group manipulates bioelectricity *without* external fields or electrodes, but through ion channel modulation (optogenetics, drugs, mutations) and gap junction control.
• Cancer cells disconnect electrically from neighbors. Forcing connection via ion channel expression can prevent tumor formation despite oncogene presence.
• The “electric face” of frog embryos prefigures facial structure, showing a bioelectric memory of the correct form. Disrupting it causes mispatterning.
• Ectopic organs (eyes, legs) can be induced by rewriting the bioelectric pattern in cells, acting as a modular “subroutine call.” Cells also recruit neighbors.

Brain Defect Repair and Planaria’s “Memories”

• A bioelectric pre-pattern determines early brain shape. Computational models guide ion channel manipulation (e.g., hcn2) to restore the pattern and correct brain defects caused by teratogens.
• Planaria (flatworms) regenerate any body part.
• Bioelectric patterns store a stable “memory” of the number of heads. Altering this (without genetic changes) creates two-headed worms.
• This altered body plan is stable through multiple cuttings, demonstrating a non-genetic, rewritable, long-term memory, analogous to incepting false memories.
• Planaria’s bioelectric circuits have multiple stable states. Work is being undertaken on the State Space and the merging formalizations between Electrical Cirtuits, Formalisms and Connectionist Architechtures
• Machine learning helps infer circuits and interventions for bioelectric control.
• Planaria can be induced to grow heads of *other* species by manipulating electrical communication, demonstrating plasticity beyond their genome’s usual expression.

Xenobots: New Life Forms From Frog Cells

• “Xenobots” are novel proto-organisms created from frog skin cells, with the *same* genome as tadpoles.
• Removed from the normal embryonic context, these cells exhibit novel behaviors and a new developmental sequence *without* eons of selection.
• This highlights the inherent potential of cells to explore “morphospace” and form new structures when constraints are removed, exploring new problems and how groups of cells could collectively adapt.

导言：超越基因

• 莱文的研究小组研究进化如何利用“多尺度能力架构”，并专注于“软件”层面（生物电），而不仅仅是“硬件”层面（DNA）。
• 生物学利用“自主材料”：细胞具有内在目标和解决问题的能力，而不仅仅是被动组件。
• 动态、强大的解剖稳态是细胞集体智慧的一种形式，在“形态空间”中解决问题。
• 发育生物电是一种关键的“认知粘合剂”，协调细胞以实现大规模的解剖结果。

“解剖编译器”——再生医学的目标

• 长期目标是一个“解剖编译器”：将所需的解剖设计转化为刺激的软件，这些刺激引导细胞构建它。
• 这将通过控制细胞群体的构建来解决主要的医学问题，如出生缺陷、损伤、癌症和衰老。
• 当前的局限性：我们缺乏仅从基因组预测解剖结构的模型，即使在嵌合胚胎中（例如，蝾螈-青蛙杂交体）。
• 医学专注于“硬件”（遗传学、通路）；理解“软件”（细胞决策）至关重要，尤其是在新的情况下。

细胞智能和稳健发育

• 胚胎发生并非硬连接：将胚胎切成两半会产生两个正常的个体，显示出适应性。
• 细胞适应内部变化：肾小管细胞适应不同的大小，通过不同的机制保持正确的管腔直径。
• 再生展示了解剖稳态：蝾螈的肢体再生到正确的尺寸并停止。
• 面部特征错位的“毕加索蝌蚪”发育成大致正常的青蛙，表明了错误纠正。
• 细胞形成网络，扩大稳态循环。单细胞目标（pH值、饥饿感）扩展到组织/器官目标（肢体长度、手指数量）。癌症涉及细胞恢复到原始的单细胞目标。

生物电：细胞通讯网络

• 细胞使用生物电，就像大脑一样，但早于神经系统：离子通道产生电位；电突触（间隙连接）促进通讯。
• 早期胚胎利用电网络在“形态空间”中指导身体计划的发育。
• 莱文的小组在*没有*外部场或电极的情况下操纵生物电，而是通过离子通道调节（光遗传学、药物、突变）和间隙连接控制。
• 癌细胞在电学上与邻近细胞断开连接。尽管存在致癌基因，但通过离子通道表达强制连接可以防止肿瘤形成。
• 青蛙胚胎的“电面”预示了面部结构，显示了正确形式的生物电记忆。破坏它会导致图案错乱。
• 可以通过重写细胞中的生物电模式来诱导异位器官（眼睛、腿），充当模块化的“子程序调用”。细胞也会招募邻近细胞。

脑缺陷修复和涡虫的“记忆”

• 生物电预模式决定了早期大脑的形状。计算模型指导离子通道操纵（例如，hcn2）以恢复模式并纠正由致畸剂引起的大脑缺陷。
• 涡虫（扁虫）再生任何身体部位。
• 生物电模式存储了头部数量的稳定“记忆”。改变这一点（没有基因变化）会产生双头蠕虫。
• 这种改变的身体计划在多次切割中是稳定的，证明了一种非基因的、可重写的、长期的记忆，类似于植入虚假记忆。
• 涡虫的生物电回路有多个稳定状态。正在进行有关状态空间以及电路、形式化和联结主义架构之间合并形式化的工作。
• 机器学习有助于推断生物电控制的电路和干预措施。
• 通过操纵电通讯，可以诱导涡虫生长*其他*物种的头部，证明了超越其基因组通常表达的可塑性。

异种机器人：来自青蛙细胞的新生命形式

• “异种机器人”是由青蛙皮肤细胞产生的新型原始生物，具有与蝌蚪*相同*的基因组。
• 从正常的胚胎环境中移除后，这些细胞表现出新的行为和新的发育序列，*无需*长时间的选择。
• 这突出了细胞在移除约束时探索“形态空间”并形成新结构的内在潜力，探索新的问题以及细胞群如何集体适应。